1. Field of the Invention
Biodegradable PEG-based hydrogels are of interest for various medical and pharmaceutical applications such as tissue regeneration, wound closure and drug delivery. For safety reasons it is strongly preferred in some applications, like for example drug delivery, to engineer biodegradability into the PEG hydrogel. Biodegradability may be introduced into a hydrogel by ester bonds that undergo spontaneous or enzymatic hydrolysis in the aqueous in vivo environment.
It is noted that citation or identification of any document in this application is not an admission that such document is available as prior art to the present invention.
Sterility of a pharmaceutical composition or a medical device intended for implantation or topical application is mandatory to receive approval as a correspondingly marketed product. Various methods of sterilization have been proposed, such as heat, pressure, filtering, chemicals or irradiation. Unfortunately, these sterilization methods are not applicable to biodegradable PEG-hydrogels as they are not compatible with retaining the hydrogel's structure and properties, thus limiting the medical use of biodegradable PEG-hydrogels.
For instance, injectable solutions are most often sterilized in their vials by autoclaving, but biodegradable bonds will undergo drastically accelerated degradation, if subjected to high temperature. Therefore, autoclaving a biodegradable PEG hydrogel will result in a pre-degraded material which will not qualify for therapeutical applications.
Alternatively, a solution may be sterilized by filtration using filters with pore sizes of 0.2 μm to remove any microbial contaminants and subsequently filling the sterile solution into the vials under aseptic conditions. However, in case of insoluble crosslinked PEG hydrogels, the material is not soluble, but may be present in form of a suspension of microparticles or as another three-dimensional object (e.g., disc or tube), typically larger in size than 0.2 μm and therefore such suspensions or gel objects cannot be sterilized by filtration.
The international patent application WO2003/035244 describes a closed-circuit apparatus which allows the preparation of sterile microparticles. Filter-sterilized chemical components are kept sterile within the aseptic environment of the system throughout the particle formation process, thus resulting in sterile microparticles.
Such aseptic processing, which applies a sterile filtration step at the level of the starting materials and maintains aseptic conditions during the process, has certain disadvantages over sterilization after the synthesis of the hydrogel, called terminal sterilization. The earlier the sterilization step occurs in the production process, the higher is the risk of accidental contamination. Aseptic processing also requires elaborate technical equipment, thus increasing production cost. Therefore, a terminal sterilization method is preferred.
Photodegradation with UV light and gamma irradiation of polymers generate radicals and/or ions that often lead to cleavage and cross-linking. Oxidation also occurs, complicating the situation, since exposure to light is seldom in the absence of oxygen. Generally, this changes the properties of the hydrogel and the material's susceptibility to biodegradation (Encyclopedia of Polymer Science and Technology, Mark Herman (Ed) Wiley, 2004, p. 263 ff).
Treatment with ethylene oxide gas or with solutions containing hydrogen peroxide will cause similar side reactions negatively affecting the hydrogel's biodegradation properties and causing substantial deviation of the degradation kinetics of the treated hydrogel as compared to the untreated hydrogel material. In addition, care has to be taken to ensure that no significant amounts of for example ethylene oxide remain in the hydrogel, which may be toxic and cause undesired side-effects.
To circumvent the difficulties associated with terminal sterilization, the processes of crosslinking and sterilization have been combined. U.S. Pat. No. 5,634,943 details a method for generating crosslinked PEG hydrogels by gamma irradiation. In this approach, linear PEG (MW 200 kDa) was dissolved in aqueous saline, degassed and irradiated by means of a gamma source such as Co60. A dosage of between 2.5 and 25 Mrads (equivalent to between 25 and 250 kGy) was sufficient to effect crosslinking of the PEG chains by radical formation and interchain linkage, resulting in a hydrated insoluble hydrogel. Due to the fact that the irradiation dosage was also sufficiently high for sterilization, in one step a material was obtained that was suitable for implantation into the cornea of the eye.
Similarly, US patent application US20090030102 describes a method of forming a crosslinked polymer gel for use in electronic devices, based on polyalkylene oxide, polyarylene oxide, or polyglycidyl ether, which in the presence of a crosslinker and organic solvent is crosslinked through UV and/or gamma irradiation.
For other applications, such as delivery of pharmaceuticals, biodegradability of the PEG hydrogel is desirable. U.S. Pat. No. 6,537,569 details a process of generating degradable PEG hydrogels through gamma irradiation. Here, linear PEG chains connected through biodegradable ester linkages are employed (MW 10 kDa). Irradiation with 25 or 30 kGy formed interchain crosslinks and an insoluble PEG hydrogel.
It was also attempted to control drug release kinetics by varying the degree of crosslinking in UV or gamma irradiated PEG hydrogels (Minkova et al., J. Polym. Sci., Polym. Phys. 27 (1989) 621-642, Belcheva et al., Macromol. Symp. 103 (1996) 193, Rosiak and Yoshii, Nuclear Instruments and Methods in Physics research B 151 (1999) 56-64, Rosiak and Ulansky, Radiation Physics and Chemistry 55 (1999) 139-151, Dimitrov et al., Acta Pharmaceutica Turcica 46 (2004) 49-54). Nevertheless, here the presence of drug during the irradiation process is required to provide for the entrapment of drug, but the possibility of irradation-caused side reactions such as oxidation or hydrolysis or conjugations to the polymer chains render this approach impractical for most therapeutic entities.
It has also been shown, that irradiation affects other properties of PEG-based hydrogels such as swelling and roughness (Kanjickal et al, J Biomed Mater Res A. 2008 Jan. 9—Effects of sterilization on poly(ethylene glycol) hydrogels).
Various PEG-based hydrogels have been described in the literature. For example, WO2006/003014 describes polymeric hydrogel conjugates of a prodrug, in which the hydrogel consists of non-biodegradable backbone moieties interconnected by crosslinkers comprising biodegradable bonds.
The European patent application EP09167026.5 describes a PEG-based hydrogel with a characteristic late-stage burst-like degradation kinetics.
A hydrogel which only consists of PEG-moieties is described in the European patent EP1019446. Hydrolytically unstable bonds are built into the hydrogel to allow degradation. The patent also claims the use of such hydrogel as a drug delivery system.
U.S. Pat. No. 5,514,379 describes, among others, PEG-based hydrogels which may contain diagnostic labels, alone or in combination with therapeutic drugs. Similarly, U.S. Pat. No. 6,602,952 describes PEG-chitosan hydrogels, containing biologically active agents which may be injected in vivo. The PCT application WO2006/38462 describes poly(ethylene oxide)-containing hydrogels with carbamate crosslinks which are used as drug delivery devices or in other biomedical functions.
It is noted that in this disclosure and particularly in the claims and/or paragraphs, terms such as “comprises”, “comprised”, “comprising” and the like can have the meaning attributed to it in U.S. Patent law; e.g., they can mean “includes”, “included”, “including”, and the like; and that terms such as “consisting essentially of” and “consists essentially of” have the meaning ascribed to them in U.S. Patent law, e.g., they allow for elements not explicitly recited, but exclude elements that are found in the prior art or that affect a basic or novel characteristic of the invention.
It is further noted that the invention does not intend to encompass within the scope of the invention any previously disclosed product, process of making the product or method of using the product, which meets the written description and enablement requirements of the USPTO (35 U.S.C. 112, first paragraph) or the EPO (Article 83 of the EPC), such that applicant(s) reserve the right to disclaim, and hereby disclose a disclaimer of any previously described product, method of making the product, or process of using the product.